Sexual reproduction depends upon accurate chromosome segregation during meiosis. Errors in segregation lead to aneuploidy and are major causes of genetic disease and spontaneous abortion in humans. Meiosis consists of two divisions preceded by a single round of DNA replication. Meiosis I is a "reductional" division in which homologous chromosomes pair and segregate to opposite poles. Meiosis II is an equational division, similar to mitosis, in which sister chromatids segregate. We have only a limited understanding of how homologous chromosomes and sister chromatids are stably connected during meiosis to permit homologous chromosomes to segregate from each other at the first division and sister chromatids to segregate at the second division. In Drosophila males, stable homolog connections require the proteins Stromalin in Meiosis (SNM) and Mod(Mdg4) in Meiosis (MNM) and sister chromatid cohesion requires the proteins Sisters Unbound (SUN) and Sisters on the Loose (SOLO). The molecular functions of these proteins are unknown. The long-term goals of this project are to gain insight into the nature of the inter-homolog and inter-sister connections that underlie meiotic segregation in Drosophila and to determine what roles SNM, MNM, SUN and SOLO play in those processes. This proposal addresses the following specific questions: 1) Are autosomal homologs connected at stable pairing sites, and if so, are SNM and MNM required for their pairing? 2) What chromosomal sites are occupied by SNM, MNM, SUN and SOLO and how do they localize to those sites? 3) What is the molecular mechanism by which SNM and MNM connect homologous chromatids? 4) What mechanisms are used by SUN and SOLO to connect sister chromatids? 5) How do SUN, SOLO, SNM and MNM interact to establish and maintain sister chromatid cohesion? Project Narrative Sexual reproduction depends upon accurate chromosome segregation during meiosis. Errors in segregation lead to aneuploidy and are major causes of genetic disease and spontaneous abortion in humans. Better understanding of the mechanisms that underlie meiotic chromosome segregation could lead to improved treatments for infertility and chromosome segregation errors.